DESCRIPTION: PD has a complex of motor and non-motor symptoms with progressive dopaminergic (DA) and non-DA neurodegeneration in multisystem. There is paucity in treatment for non-motor symptoms that include delayed gastric emptying and more prominently constipation, weight loss and reduced water intake. The underlying mechanisms are largely unknown and involve both central and peripheral alterations. Inflammation was found in the brains of PD patients, as well as animal models of PD, which may promote degeneration of DA neurons, is correlated to motor symptom severity and might contribute to the development of non-motor symptoms. An animal model for PD induced by a neurotoxin, 6-hydroxydopamine (6-OHDA) microinjected unilaterally in the medial forebrain bundle of rats, has partial loss of DA neurons. Beside motor disorders, the rats have constipation, and reduced water intake and body weight as in PD patients. We also previously reported constipation-like disorders and less weight gain in a genetic model (Thy1-asyn mice). Ghrelin is a gut hormone and it has orexigenic and prokinetic effect on the gut through peripheral and central mechanisms. PD patients with body weight loss have lower basal circulating levels of ghrelin, and do not show the late phase postprandial rise suggesting dampened ghrelin release and/or synthesis. Our preliminary data showed that systemic administration of a ghrelin agonist, anamorelin increased body weight and food intake in Thy1-aSyn mice. However, systemic ghrelin did not stimulate the colonic motility, while ghrelin agonist crossing the blood- brain barrier (BBB) did. We showed that a BBB-crossing ghrelin agonist, HM01 increased defecation in 6- OHDA rats. More importantly, ghrelin has anti-inflammatory and neuroprotective effect on DA neurons. Ghrelin agonists have advantages over ghrelin as they are orally active and long acting. The hypothesis is that ghrelin agonists have multiple beneficial effects on PD symptoms via gut prokinetic, orexigenic, dipsogenic and anabolic actions that involve distinct mechanisms. We will validate the ghrelin agonist effects in two animal models which display different PD pathological features, because no animal model recapitulates the progressive nature and complexity of human PD. The effects of BBB crossing (HM01) and non-BBB crossing (anamorelin) agonists will be compared and the targets will be assessed. (1) To assess ghrelin agonists' effect on constipation and altered colonic signals in 6-OHDA rats and Thy1-asyn mice. After oral administration of HM01 or anamorelin, fecal output and water content will be monitored, colonic motility will be measured using a non-invasive miniaturized pressure transducer. The permeability of the distal ileal and colonic mucosa will be assessed in Ussing's chambers. (2) To assess whether ghrelin agonists reduce loss of body weight and fat mass and improve feeding and water intake. HM01 and anamorelin effect in Thy1-asyn and wide type mice on food and water intake, body weight will be monitored simultaneously with energy intake and expenditure using a state-of-art automated metabolism screening system, and meal pattern by an automated feeding episode monitoring system. Ghrelin agonists' effect on body composition of Thy1-aSyn mice and 6-OHDA rats will be measured in rodent MRI equipment, as well as on water intake in 6-OHDA rats. (3) To assess ghrelin agonist effect on PD symptoms in 6-OHDA rats under L-dopa treatment, such as constipation, body weight loss, motor dysfunctions and L-dopa-induced delayed gastric emptying. The related signals in the colon and brain will be measured after ghrelin agonist and L-dopa treatment. This study will help to further validate ghrelin agonists' effect on neuroinflammation and neuroprotection in the nigrostriatal system in the animal models. Treating non- motor symptoms is one of the priorities in PD research. This project will provide preclinical evidence for novel beneficial effects of ghrelin agonists to alleviate constipation, adipsia and weight loss, as well as motor deficits in PD including Veterans who are more vulnerable under stress.